H3K4me1-Mediated Epigenomic Priming of Chemoresistant Tumor States in Ovarian Cancer

Non-genetic intratumor heterogeneity underlies therapeutic failure in cancer, yet how resistant tumor states are encoded in patients remains unclear. In this study, we show that chemoresistant evolution in high-grade serous ovarian cancer (HGSOC) is prefigured by epigenetically primed tumor cell states present before therapy. Using multimodal single-nucleus approaches, we profile transcriptional programs and histone modifications from longitudinal frozen biopsies of 16 patients with HGSOC. Tumors comprise a limited set of functional states that evolve reproducibly under chemotherapy: proliferative and IFN-responsive states are depleted, whereas TNFα-associated and epithelial-mesenchymal transition-associated programs persist or expand. Chromatin profiling reveals that these resistant programs are broadly enriched for histone H3 lysine 4 monomethylation (H3K4me1) prior to treatment, indicating that features of resistance are epigenomically primed. Baseline tumor composition is associated with survival, and fibroblast remodeling accompanies malignant adaptation. Together, these findings identify epigenomic priming as a feature of chemoresistant tumor cell states and provide a scalable framework for anticipating resistance from biopsies. SIGNIFICANCE: Using a clinically compatible multimodal single-nucleus approach, the authors show that chemoresistant evolution in HGSOC is prefigured by epigenetically primed tumor cell states present before therapy.